Control of neural crest development in Xenopus

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DESCRIPTION (provided by applicant): Sox proteins fall into a large class of transcription factors related to SRY, the testis determining factor. Expression of these proteins in defined cell types during embryogenesis appears to govern cell fate decisions. One member of this family, mouse Sox9, has been shown to regulate cartilage formation by binding and activating the chondrocyte specific enhancer of type II collagen (Col2a1). Consistent with this role, Col2a1 and Sox9 are coexpressed in all chondrogenic precursors. Mutations in Sox9 result in Campomelic Dysplasia (CD), a lethal human disorder characterized by XY sex reversal and severe skeletal malformations. During embryogenesis, Sox 9 is also expressed in neural crest progenitors. CD patients also present defects in craniofacial skeletal elements of neural crest origin (palate and jaws) suggesting that Sox9 may play an important role in cranial neural crest formation. Preliminary studies indicate that Sox9 is required for neural crest formation during Xenopus laevis development. Sox9 is expressed at the gastrula stage in the neural crest-forming region. In this tissue, Sox9 colocalizes spatially and temporally with Slug, known to be the earliest gene activated in response to neural crest-inducing signals. Depletion of Sox9 in developing embryos, using a novel antisense approach, causes a loss of neural crest progenitors and an expansion of neural tissues. Later during embryogenesis, antisense-treated embryos have a specific loss or reduction of neural crest-derived skeletal elements, mimicking aspect of the craniofacial defects observed in CD patients. Our hypothesis is that the transcription factor Sox9 is an essential component of the signaling cascade leading to neural crest formation. We propose: 1)- To characterize Sox9 activity within the neural crest by defining the timing of Sox9 requirement for neural crest formation. 2)- To determine whether Sox9 activity is required for specific neural crest lineages, by targeting Sox9 depletion in areas of the neural fold fated to form either cranial or trunk crest derivatives. 3)- To define the origin and the nature of the signals regulating Sox9 expression in the neural folds. The spectrum of abnormalities in CD patients indicates a fundamental role of Sox9 in sex determination and skeletal development but also important roles in other developmental processes. The work proposed here will address the function of Sox9 in the signaling cascade leading to neural crest formation.